* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
3: A mixture of 156 (28 g,140 mmol), formic acid (240 mL) and 37percent> concentrated HC1 (400 mL) was heated to 60 °C for 12 h, cooled in an ice-water bath, and the pH slowly adjusted to 8-9 with 28percent> concentrated NH4OH. The solid was collected by filtration, washed with water and dried in air to afford 25 g (98percent) of 5-bromo-4-methyl-lH-benzo[d]imidazole (158) as a yellow solid: MS (ESI) m/z = 213 [M+l]+.
Stage #1: at 50℃; for 2 h; Stage #2: at 20 - 70℃; for 0.5 h;
To a stirred solution of 1-bromo-2-methyl-3,4-dinitro-benzene (Tetrahedron Lett. 2000, 41(22), 4277-4279) (2.61 g, 10 mmol) in EtOH (50 mL) was added SnCl2 (1.89 g, 100 mmol). The mixture was stirred at 50° C. for 2 h. The mixture was cooled to rt, and triethylorthoformate (25 mL) was added. After heating for 30 min at 70° C., the mixture was cooled to rt, diluted with satd. aq. NaHCO3 (100 mL), and extracted with EtOAc (3.x.60 mL). The combined organic layers were washed with satd. aq. NaCl (100 mL), dried, and concentrated to give a solid residue. The residue was stirred vigorously with MeOH (100 mL) and the precipitate removed by filtration. The filtrate was concentrated to yield the crude product which was then purified by FCC (EtOAc/hexanes) to give 1.55 g (73percent) of the desired product. MS: mass calcd. for C8H7BrN2, 209.98; m/z found, 211.0 [M+H]+. 1H NMR (CD3OD): 8.18 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 2.61 (s, 3H).
To a stirred solution of 1-bromo-2-methyl-3,4-dinitro-benzene (Tetrahedron Lett. 2000, 41(22), 4277-4279) (2.61 g, 10 mmol) in EtOH (50 mL) was added SnCl2 (1.89 g, 100 mmol). The mixture was stirred at 50° C. for 2 h. The mixture was cooled to rt, and triethylorthoformate (25 mL) was added. After heating for 30 min at 70° C., the mixture was cooled to rt, diluted with satd. aq. NaHCO3 (100 mL), and extracted with EtOAc (3.x.60 mL). The combined organic layers were washed with satd. aq. NaCl (100 mL), dried, and concentrated to give a solid residue. The residue was stirred vigorously with MeOH (100 mL) and the precipitate removed by filtration. The filtrate was concentrated to yield the crude product which was then purified by FCC (EtOAc/hexanes) to give 1.55 g (73percent) of the desired product. MS: mass calcd. for C8H7BrN2, 209.98; m/z found, 211.0 [M+H]+. 1H NMR (CD3OD): 8.18 (s, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 2.61 (s, 3H).
3: A mixture of 156 (28 g,140 mmol), formic acid (240 mL) and 37percent> concentrated HC1 (400 mL) was heated to 60 °C for 12 h, cooled in an ice-water bath, and the pH slowly adjusted to 8-9 with 28percent> concentrated NH4OH. The solid was collected by filtration, washed with water and dried in air to afford 25 g (98percent) of 5-bromo-4-methyl-lH-benzo[d]imidazole (158) as a yellow solid: MS (ESI) m/z = 213 [M+l]+.
4-Bromo-3-methyl-1,2-benzenediamine (6.89 g, 34.3 mmol), formic acid (60 ml) and 37percent concentrated HCl (150 ml) were heated at 60° C. for 12 h, cooled in an ice-water bath, and slowly adjusted with 28percent concentrated ammonium solution (280 ml) to pH8-9. The solid was collected by filtration, washed with water and dried in air to afford the title compound as a pinkish white solid.1H NMR (400 MHz, DMSO-d6) delta ppm 2.58 (s, 3H) 7.32 (s, 2H) 8.20 (s, 1H) 12.62 (br., 1H); (M+1) 212.94, 1.11 min (LC/MS method A)
<strong>[952511-48-7]5-Bromo-4-methyl-1H-benzimidazole</strong> (6.62 g, 31.36 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml) and cooled to 0° C. Sodium hydride oil dispersion (60percent, 1.55 g, 38.75 mmol) was slowly added. The mixture was stirred for 1 h at 0° C. Triphenylmethyl chloride and a catalytic amount of tetrabutylammonium iodide were added. The resultant mixture was heated at reflux for 12 h, cooled to room temperature, quenched with saturated ammonium chloride solution (50 ml) and partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in 50 ml of 50percent ethyl acetate in hexanes, heated to reflux, cooled to room temperature and filtered to afford the title compound as a pale brown solid. The filtrate was concentrated and purified by silica gel column chromatography (5 to 20percent ethyl acetate in hexanes) to give more title compound.1H NMR (400 MHz, CDCl3) delta ppm 2.70 (s, 3H) 6.19 (d, 1H) 7.00-7.20 (m, 7H) 7.20-7.45 (m, 9H) 7.92 (s, 1H); LC-MS: (Ph3C+) 243.11, 3.27 min (LC/MS method A)
With toluene-4-sulfonic acid; In tetrahydrofuran; at 80℃;
Example 46N4-(5-Cyclopropyl- 1 H-pyrazol-3-yl)-N2-methyl-N2-((4-methyl- 1 H-b enzo [d] imidazol-5- yl)methyl)pyrimidine-2,4-diamine (1-95)step 1 : To a solution of 5-bromo-4-methyl-lH-benzo[d]imidazole (1.0 g, 4.74 mmol, CASRN 952511-48- 7) and 3,4-dihydro-2H-pyran (2.0 g, 23.70 mmol) in THF (10 mL) was added / TsOH-H20 (90 mg, 0.47 mmol). The mixture was heated at 80 °C overnight, cooled and the solvent was removed in vacuo. The residue was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried (MgSO i), filtered and concentrated to dryness in vacuo. The crude product was purified by Si02 chromatography eluting with a petroleum ether/EtOAc gradient (10 to 50percent EtOAc) to afford 800 mg (57percent) of 5-bromo-4-methyl-l -(tetrahydro- 2H-pyran-2-yl)-lH-benzo[d]imidazole (254) as light yellow solid: MS (ESI) m/z = 295.1 [M+l]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; zinc; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere;
step 4: A mixture of 158 (21 g; 99 mmol), Zn(CN)2 (23.2 g; 198 mmol), Pd(dppf)Cl2 (6.4 g; 9.9 mmol) and zinc (258 mg; 4 mmol) in dry DMF (150 mL) under inert atmosphere was heated at 120 °C for 2 h. The reaction mixture was filtered through a pad of Celite® that was washed with EtOAc. The organics were washed with water, dried (MgSO i), filtered and evaporated in vacuo. The crude product was purified by Si02 chromatography eluted with a DCM/MeOH gradient (0 to 10percent> MeOH) to afford 8.3 g (53percent>) of 4-methyl-lH-benzo[d]imidazole-5-carbonitrile (160) as a brown solid: MS (ESI) m/z = 158 [M+l]+.
benzyl (2R,3S)-2-(3-bromo-2-oxopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate[ No CAS ]
benzyl (2R,3S)-2-(3-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)-2-oxopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
5-Bromo-4-methyl-lH-benzo[d]imidazole (86.53 mg, 0.41 mmol) was dissolved in N,N-dimethylformamide (2 mL, 0.20 M) to which potassium carbonate (114.09 mg, 0.83 mmol) was added and then stirred at room temperature for 10 minutes. Then, benzyl (2R,3S)-2- (3 -bromo-2-oxopropyl)-3-((tert-butyldimemylsilyl)oxy)piperidine-l -carboxylate (200 mg, 0.41 mmol) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the solvent was removed and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane:ethylacetate = 5:1) to give the title compound (217 mg, yield: '86percent)
benzyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(5-(3-fluorophenyl)-4-methyl-1H-benzo[d]imidazol-1-yl)-2-oxopropyl)piperidine-1-carboxlate[ No CAS ]
tert-butyl (2R,3S)-2-(3-bromopropyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate[ No CAS ]
tert-butyl (2R,3S)-2-(3-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)propyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;
Tert-butyl (2R,3S)-2-(3-bromopropyl)-3-((tert-butyldimemylsilyl)oxy)piperidine-l- carboxylate (40 mg, 0.09 mmol) obtained from Step 1-5 of Example 1 was dissolved in N,N- dimethylformamide (2 niL, 0.05 M). Then, potassium carbonate (25 mg, 0.18 mmol) and 5- bromo-4-methyl-lH-benzo[d]imidazole (18 mg, 0.09 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 1 : 1) to give the title compound (43 mg, yield: 85percent).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
